X-distjbstituted j-amino-s-halogen-



Patented Apr. 21, 1953 4,4-DI'SUBSTITUTED 3-AMINO-5-HALOGEN- PYRAZOLES Jean Druey,,Riehen, Switzerland, assignor to Ciba Pharmaceutical Products, Inc., Summit, N. J.

No Drawing. Application January 8, 1951, Serial No. 205,037. In Switzerland February 13,1950

Claims.

The present invention relates to new 4,4-disubstituted 3-amino-5 -halogen-pyrazoles which correspond to the type formula Helios 2N or, in the tautomeric form, to the type formula R1 R2C=NH HaI-C NH wherein R1 is a lower aliphatic hydrocarbon group containing a maximum of 3 carbon atoms, R2 is an aliphatic or a mononuclear alicyclic or mononuclear aromatic hydrocarbon radical, and

Hal is a chlorine or bromine atom. The invention relates also to salts of the aforedescribed compounds.

These compounds, and particularly 3-a:r 1ino4- methyll-n-butyl-Bbromo-pyrazole and 3-ami- "no4-methyl-4-n-buty1-5-chloro-pyrazole, exert a sedative action.

The new aminopyrazoles are obtained by treating an aminopyrazolone which corresponds to the formula Depending upon the procedure employed, the i new compounds are obtained as bases or in the form of their salts. From the latter, the free bases can be obtained in conventional manner. From the bases, on the other hand, it is also p0..-

sible to prepare salts with the most diverse acids,

inorganic (for example, hydrochloric acid, phosphoric acid, etc.) as well as organic (for example, tartaric acid, methanesulfonic acid, etc). Particularly suitable are those acids which have been used therapeutically, such for example as hydrobromic acid, salicylic acid, acetylsalicylic acid. etc.- o

The invention is described in greater detail in the following illustrative examples. Parts by weight bear the same relation to parts by volume as do grams to cubic centimeters. Tempera tunes are in degrees centigrade. Percentages are by weight.

Example 1 5 parts by weight of 3 -amino-4,4-diethylpyr-azolone- (5), prepared from diethylcyanoacetic acid-ethyl ester and hydrazine, are heated on a boiling water-bath for .2 hours with parts by volume of phosphorus oxychloride, dissolution taking place gradually. Upon completion of the reaction, the greatest part of the excess phosphorus oxychloride is distilled off in va-cuo, and water is added to the residue, the reaction mixture being allowed to reach a temperature of about 60. Any undissolved impurities are removed by filtration, and an excess of aqueous caustic soda solution of 10% concentration is added to the acid filtrate. The reaction mixture is then cooled to about and the crystallized 3-amino-4,4-diethyl-5chloro-pyrazole of the formula CaHa C2'H5CC-NH2 Example 2 4.3 parts by weight of a 3-amino-4-n butyl-4- methyl-'pyrazolone-(Ev), prepared from n-butylmethyl-cyanoacetic acid ethyl ester by reaction with hydrazine, are triturated with 8.6 parts by weight of phosphorus pentabromide and thereupon gradually heated to 100. Upon further heating atthis temperature, th mixture liquefles and finallybecomes a solid again. After 2 hours, the mass is allowed to cool and the excess of phosphorus bromide decomposed with ice water. After digesting for along time, the hydrob-romide of 3 amino 4 n butyl 4 methyl 5 bromo-pyrazole separates out in well crystallized form and in good yield. After recrystallization from water, it is pure and melts at 206-20'7.

10 parts by Weight of the hydrobromide are dissolved in parts of warm water. Aqueous ammonia in excess is then added to the solution which is then suction-filtered. After recrystal- 3 lization from water, the obtained free 3-amino-4- n-butyl-4-methyl-5-bromo-pyrazole of the formula.

melts at 144-146.

Example 3 5 parts by weight of 3-amino-4-phenyl-4- 'ethyl-pyrazolone-(5) and 20 parts by volume of phosphorus oxychloride are heated to 100 for 3 hours, solution taking place. The cooled reaction mixture is decomposed with ice, and then an excess of aqueous ammonia solution is added. After standing for 2 days, the precipitated product is extracted with chloroform, the chloroform solution is shaken out with 2-normal aqueous caustic soda solution while cooling and is then evaporated to dryness. Recrystallized from methanol, a good yield of 3-amino-4-phenyl-4- ethy1-5-ch1oro-pyrazole of the formula C2115 C aHr- C-NH! is obtained; it melts at 163-165".

Example 4 By proceeding in the manner described in Examples 1 to 3, employing corresponding quantities of starting materials of the formula.

ih Be o a-NH, 'o= N and of phosphorus oxychloride or phosphorus oxybromide, the corresponding products of the type formula and of the composition shown in the following table are obtained:

R1 R2 Hal Melting Point n-butyl C1 157 iso-butyl- Cl 168 do Br 157159 heptyl Cl 157 cyclohexcnyl. O1 180 eth Br 165 Cl 152-153 Br 185 Br Approx. 145 n-propyl. Cl 174 do Br 162-163 01 167 Br 160 01 150 01 loo-162 The other formulas may also be analogously reproduced.

Having thus disclosed the invention, what is claimed is:

1. A member selected from the class consisting of the 4,4-disubstituted 3-amino-5-halogen pyrazoles which correspond to the formulae R1 R ,-ONH: Hal- 111 and R Rz-C'JO=NH Ha1 NH and their salts, wherein R1 is a lower aliphatic hydrocarbon group with at most 3 carbon atoms, R2 is a member selected from the group consisting of alkyl, cycloalkyl and mononuclear aromatic carbocyclic hydrocarbon radicals, and Hal is selected from the group consisting of chlorine and bromine.

2. 3- amino- 4 methyl- 4-nbutyl 5- bromopyrazole. Y

3. An acid salt of 3-amino-4-methyl-4-n-buty1-5-bromo-pyrazolc.

4. The hydrobromide of 3-amino-4-methyl-4- n-butyl-5-bromo pyrazole.

5. 3- amino 4- methyl- 4-.nbutyl- 5- chloropyrazole.

JEAN DRUEY.

References Cited in the file or this patent Chemical Abstracts, Vol. 8, p. 691, citing Berichte 46, p. 3612.5.

Gagnon, Canadian Journal Research, vol. 27B (1949), pp. -20; 

1. A MEMBER SELECTED FROM THE CLASS CONSISTING OF THE 4,4-DISUBSTITUTED 3-AMINO-5-HALOGENPYRAZOLES WHICH CORRESPOND TO THE FORMULAE 